The mitochondrial unfolded protein response in human microglia disrupts neuronal–glial communication and promotes senescence
12 affiliations
- 1Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. [email protected]
- 2Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany. [email protected]
- 3Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, Paris, France. [email protected]
- 4Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, Paris, France
- 5Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
- 6Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
- 7Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR 3633, Paris, France
- 8Department of Clinical Sciences and Community Health, Excellence Department 2023-2027, University of Milan, Milan, Italy
- 9Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy
- 10Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
- 11Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. [email protected]
- 12Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, Paris, France. [email protected]
Abstract
Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPR mt ) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPR mt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal–glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPR mt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPR mt in neurodegenerative disease pathogenesis.
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BibTeX
@article{perez2026mitochondrial,
title = {{The mitochondrial unfolded protein response in human microglia disrupts neuronal–glial communication and promotes senescence}},
author = {Maria Jose Perez J. and Alicia Lam and Christin Weissleder and Federico Bertoli and Hariam Raji and Mariella Bosch and Ivan Nemazanyy and Stefanie Kalb and Mohammed Kehili and Insa Hirschberg and Dario Brunetti and Indra Heckenbach and Morten Scheibye‐Knudsen and Michela Deleidi},
journal = {Nature Neuroscience},
year = {2026},
month = jun,
doi = {10.1038/s41593-026-02320-1},
url = {https://doi.org/10.1038/s41593-026-02320-1},
note = {CC BY},
}
RIS
TY - JOUR
TI - The mitochondrial unfolded protein response in human microglia disrupts neuronal–glial communication and promotes senescence
AU - Maria Jose Perez J.
AU - Alicia Lam
AU - Christin Weissleder
AU - Federico Bertoli
AU - Hariam Raji
AU - Mariella Bosch
AU - Ivan Nemazanyy
AU - Stefanie Kalb
AU - Mohammed Kehili
AU - Insa Hirschberg
AU - Dario Brunetti
AU - Indra Heckenbach
AU - Morten Scheibye‐Knudsen
AU - Michela Deleidi
PY - 2026
DA - 2026/06/26
JO - Nature Neuroscience
DO - 10.1038/s41593-026-02320-1
UR - https://doi.org/10.1038/s41593-026-02320-1
AB - Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPR mt ) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPR mt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal–glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPR mt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPR mt in neurodegenerative disease pathogenesis.
SN - 1097-6256
SN - 1546-1726
ER -